Disrupted BRCA1-PALB2 interaction induces tumor immunosuppression and T-lymphocyte infiltration in HCC through cGAS-STING pathway
Disrupted BRCA1-PALB2 interaction induces tumor immunosuppression and T-lymphocyte infiltration in HCC through cGAS-STING pathway
复制标题
阻断BRCA1-PALB2相互作用可通过cGAS-STING途径诱导肝癌肿瘤免疫抑制和t淋巴细胞浸润
DOI：
10.1002/hep.32335
复制
发表时间：
2022-02-15
期刊：
影响因子：
13.5
通讯作者：
Xia, Bing
中科院分区：
文献类型：
--
作者：
Ma, Hui;Kang, Zhihua;Xia, Bing
背景和目标：BRCA 1（BRCA 1 DNA修复相关）和PALB 2（BRCA 2的伴侣和定位子）相互作用，促进同源重组和DNA双链断裂修复。据报道，这种相互作用的破坏在肿瘤发生中起作用。然而，它在HCC中的确切功能仍然知之甚少。方法和结果：我们证明，破坏BRCA 1-PALB 2相互作用的小鼠比野生型小鼠更容易患肝癌。从这些小鼠产生的HCC肿瘤显示出大量的T淋巴细胞浸润和对程序性细胞死亡1（PD-1）抗体治疗的更好反应。从机制上讲，BRCA 1-PALB 2相互作用的破坏导致HCC细胞中持续高水平的DNA损伤，导致肿瘤微环境中恶性肝细胞和M1巨噬细胞中的环GMP-AMP合酶（cGAS）-干扰素基因（STING）信号通路的激活。激活的cGAS-STING途径通过STING-干扰素调节因子3（IRF 3）-信号转导子和转录激活因子1途径诱导程序性细胞死亡1配体1表达，引起免疫抑制以促进肿瘤发生和肿瘤进展。同时，具有激活的cGAS-STING通路的M1巨噬细胞可以通过STING-IRF 3通路募集T淋巴细胞，导致肿瘤中的T淋巴细胞浸润。PD-1抗体治疗使免疫反应正常化后，浸润的T淋巴细胞迅速有效地攻击肿瘤细胞。结论：本研究揭示了由缺陷的BRCA通路引起的持续DNA损伤通过cGAS-STING通路诱导HCC中的肿瘤免疫抑制和T淋巴细胞浸润，从而深入了解肿瘤免疫微环境重塑，这可能有助于改善HCC对PD-1抗体治疗的反应。
Background and Aims: BRCA1 (BRCA1 DNA repair associated) and PALB2 (partner and localizer of BRCA2) interact with each other to promote homologous recombination and DNA double-strand breaks repair. The disruption of this interaction has been reported to play a role in tumorigenesis. However, its precise function in HCC remains poorly understood.Approach and Results: We demonstrated that mice with disrupted BRCA1-PALB2 interaction were more susceptible to HCC than wild-type mice. HCC tumors arising from these mice showed plenty of T-lymphocyte infiltration and a better response to programmed cell death 1 (PD-1) antibody treatment. Mechanistically, disruption of the BRCA1-PALB2 interaction causes persistent high level of DNA damage in HCC cells, leading to activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway in both malignant hepatocytes and M1 macrophages in the tumor microenvironment. The activated cGAS-STING pathway induces programmed cell death 1 ligand 1 expression via the STING-interferon regulatory factor 3 (IRF3)-signal transducer and activator of transcription 1 pathway, causing immunosuppression to facilitate tumorigenesis and tumor progression. Meanwhile, M1 macrophages with an activated cGAS-STING pathway could recruit T lymphocytes through the STING-IRF3 pathway, leading to T-lymphocyte infiltration in tumors. After normalizing immune responses by PD-1 antibody treatment, the infiltrating T lymphocytes attack tumor cells rapidly and effectively.Conclusions: This study reveals that persistent DNA damage caused by a defective BRCA pathway induces tumor immunosuppression and T-lymphocyte infiltration in HCC through the cGAS-STING pathway, providing insight into tumor immune microenvironment remodeling that may help improve HCC response to PD-1 antibody treatment.